title: Role of the viral hemagglutinin in the anti-influenza virus activity of newly synthesized polycyclic amine compounds.
abstract: We here report on the synthesis of new series of polycyclic amines initially designed as ring-rearranged analogs of amantadine and featuring pentacyclo, hexacyclo, and octacyclo rings. A secondary amine, 3-azahexacyclo[7.6.0.0¹,⁵.0⁵,¹².0⁶,¹⁰.0¹¹,¹⁵]pentadeca-7,13-diene, 3, effectively inhibited A/M2 proton channel function, and, moreover, possessed dual activity against an A/H3N2 virus carrying a wild-type A/M2 proton channel, as well as an amantadine-resistant A/H1N1 virus. Among the polycyclic amines that did not inhibit influenza A/M2 proton channel function, several showed low-micromolar activity against tested A/H1N1 strains (in particular, the A/PR/8/34 strain), but not A/H3N2 influenza viruses. A/PR/8/34 mutants selected for resistance to these compounds possessed mutations in the viral hemagglutinin that markedly increased the hemolysis pH. Our data suggest that A/H1N1 viruses such as the A/PR/8/34 strain are particularly sensitive to a subtle increase in the endosomal pH, as caused by the polycyclic amine compounds.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Diagonal 643, Barcelona E-08028, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Torres
authors.forename: María D
authors.initials: MD
authors.lastname: Duque
authors.forename: Evelien
authors.initials: E
authors.lastname: Vanderlinden
authors.forename: Chunlong
authors.initials: C
authors.lastname: Ma
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Pinto
authors.forename: Pelayo
authors.initials: P
authors.lastname: Camps
authors.forename: Mathy
authors.initials: M
authors.lastname: Froeyen
authors.forename: Santiago
authors.initials: S
authors.lastname: Vázquez
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
mesh_terms: D000547:Amantadine; D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology*; D015394:Molecular Structure; D011083:Polycyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011083:Polycyclic Compounds; D000547:Amantadine
keywords: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; Amantadine; Amt; CPE; HA; HRMS; Hemagglutinin; Influenza A virus; M2 protein; MDCK; MTS; Madin–Darby canine kidney; N-methyl-d-aspartate; NMDA; Polycyclic amines; TEV; TM; amantadine; cytopathic effect; hemagglutinin; high resolution mass spectra; transmembrane; two-electrode voltage clamps; wild-type; wt